The fat body cortical actin network regulates Drosophila inter-organ nutrient trafficking, signaling, and adipose cell size
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Curated by eLife
Evaluation Summary:
The authors explore how the actin network in the fat body impacts nutrient uptake in multiple ways. Overall, this is an interesting study that sheds light on adipocyte cytoskeletal dynamics and it's impact on nutrient trafficking and fat body storage. The work can be further strengthened by additional validation of tools and data.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)
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Abstract
Defective nutrient storage and adipocyte enlargement (hypertrophy) are emerging features of metabolic syndrome and type 2 diabetes. Within adipose tissues, how the cytoskeletal network contributes to adipose cell size, nutrient uptake, fat storage, and signaling remain poorly understood. Utilizing the Drosophila larval fat body (FB) as a model adipose tissue, we show that a specific actin isoform—Act5C—forms the cortical actin network necessary to expand adipocyte cell size for biomass storage in development. Additionally, we uncover a non-canonical role for the cortical actin cytoskeleton in inter-organ lipid trafficking. We find Act5C localizes to the FB cell surface and cell-cell boundaries, where it intimately contacts peripheral LDs (pLDs), forming a cortical actin network for cell architectural support. FB-specific loss of Act5C perturbs FB triglyceride (TG) storage and LD morphology, resulting in developmentally delayed larvae that fail to develop into flies. Utilizing temporal RNAi-depletion approaches, we reveal that Act5C is indispensable post-embryogenesis during larval feeding as FB cells expand and store fat. Act5C-deficient FBs fail to grow, leading to lipodystrophic larvae unable to accrue sufficient biomass for complete metamorphosis. In line with this, Act5C-deficient larvae display blunted insulin signaling and reduced feeding. Mechanistically, we also show this diminished signaling correlates with decreased lipophorin (Lpp) lipoprotein-mediated lipid trafficking, and find Act5C is required for Lpp secretion from the FB for lipid transport. Collectively, we propose that the Act5C-dependent cortical actin network of Drosophila adipose tissue is required for adipose tissue size-expansion and organismal energy homeostasis in development, and plays an essential role in inter-organ nutrient transport and signaling.
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Evaluation Summary:
The authors explore how the actin network in the fat body impacts nutrient uptake in multiple ways. Overall, this is an interesting study that sheds light on adipocyte cytoskeletal dynamics and it's impact on nutrient trafficking and fat body storage. The work can be further strengthened by additional validation of tools and data.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)
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Reviewer #1 (Public Review):
Ugrankar et al provide an interesting article exploring the impact of the actin network in adipocyte cell size and nutrient uptake. The manuscript is well written and presents gaps in current knowledge well. The authors use Drosophila to address their research questions, describing a specific isoform of actin, Actin 5C, as the critical mediator of lipid metabolism in the larval fat body. In support, they show that loss of a mediator of actin dynamics, twinfilin, can have similar impacts as actin 5C loss. The authors further probe for impacts of additional cytoskeletal proteins, spectrins, in this process, concluding that spectrin activity differs from Actin 5C. Last, the authors attempt to explore how actin network in the fat body impacts nutrient uptake in multiple ways. Overall, this is an interesting …
Reviewer #1 (Public Review):
Ugrankar et al provide an interesting article exploring the impact of the actin network in adipocyte cell size and nutrient uptake. The manuscript is well written and presents gaps in current knowledge well. The authors use Drosophila to address their research questions, describing a specific isoform of actin, Actin 5C, as the critical mediator of lipid metabolism in the larval fat body. In support, they show that loss of a mediator of actin dynamics, twinfilin, can have similar impacts as actin 5C loss. The authors further probe for impacts of additional cytoskeletal proteins, spectrins, in this process, concluding that spectrin activity differs from Actin 5C. Last, the authors attempt to explore how actin network in the fat body impacts nutrient uptake in multiple ways. Overall, this is an interesting study that sheds light on adipocyte cytoskeletal dynamics. However, there are a number of concerns, including: a need to validate the many RNAi used, the need to add data to rule out a potential contribution from other actin isoforms, further characterization of the assays used to address nutrient uptake, and further validation of the data used to argue that actin 5C is not essential during embryogenesis.
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Reviewer #2 (Public Review):
In this study, by interrogating the cytoskeletal organization of adipocytes, Ugrankar et al. reveal a specific role for an Actin isoform in the organization of the cortical cytoskeleton. They note that while both actin and spectrin (another cytoskeletal element) are required for the cellular organization of adipocyte periphery, they note a specific role for Act5c (one of the six actin isoforms in Drosophila), and a filamentous actin organizer Twf in regulating both organization as well as in fat storage. Hence, only actin but not spectrin is required for fat storage. They find that tissue-specific disruption of Twf or Act5c causes reduced fat storage but did not affect the ability of fat cells to take up carbohydrates and lipids. Furthermore, their experiments imply a possible role for Act5c and Twf in the …
Reviewer #2 (Public Review):
In this study, by interrogating the cytoskeletal organization of adipocytes, Ugrankar et al. reveal a specific role for an Actin isoform in the organization of the cortical cytoskeleton. They note that while both actin and spectrin (another cytoskeletal element) are required for the cellular organization of adipocyte periphery, they note a specific role for Act5c (one of the six actin isoforms in Drosophila), and a filamentous actin organizer Twf in regulating both organization as well as in fat storage. Hence, only actin but not spectrin is required for fat storage. They find that tissue-specific disruption of Twf or Act5c causes reduced fat storage but did not affect the ability of fat cells to take up carbohydrates and lipids. Furthermore, their experiments imply a possible role for Act5c and Twf in the secretion of lipoprotein -Apolpp (the homolog of human ApoB).
In addition, the following interesting leads in this study, while intriguing, need further confirmation and clarification.
1. The role of Act5c/Twf in gut-fat communication via lipoprotein delivery from fat tissue is an exciting lead but would need further genetic and functional analyses.
2. Act5c is specifically required for lipoprotein trafficking but not carbohydrate transporters to reach the periphery is intriguing but requires further testing.
3. Additional confirmation is required to exclude the role of other actin isoforms in cytoskeletal organization.
Suppose authors can clarify and deepen all these exciting leads by further experimentation. Then, their findings on the requirement of cortical organization for appropriate endocrine activities of the adipose tissue have broad implications for cell biology, lipid biology, and organismal homeostasis.
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